Genetic Variant SNX22:p.His51Pro (chr15-64152319-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024798.3(SNX22):c.152A>C(p.His51Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000734 in 1,362,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H51R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

SNX22
NM_024798.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.79

Publications

0 publications found

Variant links:

Genes affected

SNX22 (HGNC:16315): (sorting nexin 22) The protein encoded by this gene is a sorting nexin that is found in the cytoplasm, where it interacts with membrane-bound phosphatidylinositol 3-phosphate. The encoded protein may play a role in intracellular trafficking. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Dec 2012]

SNX22 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024798.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNX22	NM_024798.3	MANE Select	c.152A>C	p.His51Pro	missense	Exon 2 of 7	NP_079074.2	Q96L94-1
	SNX22	NR_073534.2		n.197A>C		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNX22	ENST00000325881.9	TSL:1 MANE Select	c.152A>C	p.His51Pro	missense	Exon 2 of 7	ENSP00000323435.4	Q96L94-1
SNX22	ENST00000560945.1	TSL:1	n.576A>C		non_coding_transcript_exon	Exon 1 of 4
SNX22	ENST00000898205.1		c.76-319A>C		intron	N/A	ENSP00000568264.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000899

AC:

AN:

111270

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000457

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.34e-7

AC:

AN:

1362790

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

671982

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29372

American (AMR)

AF:

0.0000304

AC:

AN:

32898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23942

East Asian (EAS)

AF:

0.00

AC:

AN:

34256

South Asian (SAS)

AF:

0.00

AC:

AN:

76724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070592

Other (OTH)

AF:

0.00

AC:

AN:

56916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.065

MutationAssessor

Pathogenic

3.9

PhyloP100

3.8

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-8.1

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.70

Vest4

0.86

MutPred

0.85

Gain of methylation at K56 (P = 0.0497)

MVP

0.72

MPC

0.52

ClinPred

1.0

GERP RS

5.2

Varity_R

0.92

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over